Author(s): K. H. Holt;L. E. Lim;V. Straub;D. P. Venzke;F. Duclos;R. D. Anderson;B. L. Davidson;K. P. Campbell
Abstract: Four types of limb-girdle muscular dystrophy (LGMD) are known to be caused by mutations in distinct sarcoglycan genes. The BIO 14.6 hamster is a model for sarcoglycan-deficient LGMD with a deletion in the delta-sarcoglycan (delta-SG) gene. We investigated the function of the sarcoglycan complex and the feasibility of sarcoglycan gene transfer for LGMD using a recombinant delta-SG adenovirus in the BIO 14.6 hamster. We demonstrate extensive long-term expression of delta-sarcoglycan and rescue of the entire sarcoglycan complex, as well as restored stable association of alpha-dystroglycan with the sarcolemma. Importantly, muscle fibers expressing delta-sarcoglycan lack morphological markers of muscular dystrophy and exhibit restored plasma membrane integrity. In summary, the sarcoglycan complex is requisite for the maintenance of sarcolemmal integrity, and primary mutations in individual sarcoglycan components can be corrected in vivo.
Keywords: Adenoviridae Animals Cricetinae Cytoskeletal Proteins/ genetics Gene Transfer Techniques Humans Injections, Intramuscular Male Membrane Glycoproteins/ genetics Microinjections Muscle Fibers/chemistry/physiology Muscle, Skeletal/chemistry/cytology/physiopathology Muscular Dystrophy, Animal/ genetics/ therapy Mutation/physiology Plasmids/pharmacology Recombinant Proteins/pharmacology Sarcoglycans Sarcolemma/physiology